Abstract:

Background: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties.

Objective: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested.

Method: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg).

Results: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate.

Conclusion: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.